Analysis of Systemic and Cutaneous Inflammatory Immune Response in Canine Atopic Dermatitis
Background: Canine atopic dermatitis (CAD) is a chronic and inflammatory disease present in veterinary dermatological practice. The inflammation in CAD is triggered by environmental allergens and skin microorganisms, which are responsible for the worsening of cutaneous lesions. This continuous activation of skin inflammatory process can induce the production of free radicals that also contribute to cellular damage and ultimately leads to changes in blood parameters in dogs with CAD. Although there are reports of inflammatory parameters in CAD, there are a lack of studies correlating skin lesions, blood leukocytes and oxidative stress. Based on that,this study aimed to evaluate the integumentary and systemic inflammatory response in dogs with atopic dermatitis.
Materials, Methods & Results: Dogs with confirmed diagnosis of canine atopic dermatitis (n = 10) were divided in two groups according to CADESI-IV: AI, with CADESI between 0-10, AII, with CADESI between 10-34, and control group (n = 5). Blood-biochemical and histological analysis were performed to access systemic and cutaneous inflammatory response. AII group tended to higher neutrophil and eosinophil counts, as well as neutrophil/lymphocyte ratio (NLR) when compared to AI. The albumin was lower in AII compared to AI and control (P < 0.05), while total bilirubin and malondialdehyde (MDA) did not differ between groups. NLR (r = 0.64 and P = 0.04) and MDA (r = 0.54 and P = 0.1) were positively correlated with CADESI, while albumin was negatively correlated with CADESI (r = -0.79 and P = 0.005). Histopathological analysis revealed a larger number of neutrophils, macrophages and mast cells in AI and AII than in control group (P < 0.05).
Discussion: In this study it was possible to evaluate the systemic and cutaneous leukocyte dynamics in CAD. Skin inflammation induces the production of chemotactic molecules contribute to neutrophil outflow from blood vessel toward the affected tissue, which can be visualized as perivascular inflammatory infiltrate and exocytosis. At systemic level, there was a tendency to increase in total leukocytes and circulating neutrophil count in group AII, as well as in neutrophil/lymphocyte ratio (NLR), when compared to AI. The NLR is a widely available and inexpensive laboratory biomarker that quantifies systemic inflammation, being used in human medicine to evaluate prognosis in different types of cancer. In our study, dogs in AII group showed an increased NLR compared to AI and control, which demonstrates the influence of skin injury in systemic parameters. Furthermore, AII group is composed of dogs with greater lesion state, which reflects in higher NLR values. Since this disease is known by its chronicity and may remain stable for years, NLR may be a novel biomarker to evaluate acute exacerbation in CAD and could potentially explain why some patients have longer crisis duration and frequent flares. The maintenance of the inflammatory state also induces the production of oxidizing substances, which possibly exceed the total antioxidant capacity, generating a situation of oxidative stress, which can result in damage to membrane lipids and release of their products. MDA is reliable and is the most commonly used marker of the overall lipid peroxidation level and the presence of oxidative stress. This result may be related with the antioxidant system, such as albumin and bilirubin, which was able to promote an efficient control of oxidant substances. In conclusion, the presented data demonstrated an inflammatory process progression as well as introduced NLR as a potential marker of disease exacerbation in CAD.
Ahmadi Z., Hassanshahi G., Khorramdelazad H., Zainodini N. & Koochakzadeh L. 2016. An overlook to the characteristics and roles played by eotaxin net- work in the pathophysiology of food allergies: allergic asthma and atopic dermatitis. Inflammation. 39: 1253-1267.
Almela R.M., Rubio C.P., Ceron J.J., Anson A., Tichy A. & Mayer U. 2018. Selected serum oxidative stress biomarkers in dogs with non-food-induced and food-induced atopic dermatitis. Veterinary Dermatology. 29: 229-e82.
Amber K.T., Chernyavsky A., Agnoletti A.F., Cozzani E. & Grando S.A. 2018. Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes. Experimental Dermatology. 27: 1322-1327.
Amber K.T., Valdebran M., Kridin K. & Grando S.A. 2018. The role of eosinophils in bullous pemphigoid: a developing model of eosinophil pathogenicity in mucocutaneous disease. Frontiers in Medicine. 5: 201.
Bertino L., Guarneri F., Cannavò S.F., Casciaro M., Pioggia G. & Gangemi S. 2020. Oxidative Stress and Atopic Dermatitis. Antioxidants. 9: 196.
Chermprapai S., Ederveen T.H.A., Broere F., Broens E.M., Schlotter Y.M., Schalkwijk S.V., Boekhorst J., van Hijum S.A.F.T. & Rutten V.P.M.G. 2019. The bacterial and fungal microbiome of the skin of healthy dogs and dogs with atopic dermatitis and the impact of topical antimicrobial therapy, an exploratory study. Veterinary Microbiology. 229: 90-99.
Cork M.J., Danby S.G., Vasilopoulos Y., Hadgraft J., Lane M.J., Moustafa M., Guy R.H., MacGowan O.L., Tazi-Ahnini R. & Ward S.J. 2009. Epidermal Barrier Dysfunction in Canine Atopic Dermatitis. Journal of Investigative Dermatology. 129: 1892-1908.
Deng Q., He B., Liu X., Yue J., Ying H., Pan Y., Sun H., Chen J., Wang F., Gao T., Zhang L. & Wang S. 2015. Prognostic value of pre‐operative inflammatory response biomarkers in gastric cancer patients and the construction of a predictive model. Journal of Translational Medicine. 13: 66.
Draper H.H. & Hadley M. 1990. Malondialdehyde determination as index of lipid peroxidation. Methods in Enzymology. 186: 421-431.
Favrot C., Fischer N., Olivry T., Zwickl L., Audergon S. & Rostaher A. 2019. Atopic dermatitis in West Highland white terriers – part I: natural history of atopic dermatitis in the first three years of life. Veterinary Dermatology. 31(2): 106-110.
Favrot C., Steffan J., Seewald W. & Picco F. 2010. A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis. Veterinary Dermatology. 21: 23-31.
Fuchs J., Zollner T.M., Kaufmann R. & Podda M. 2001. Redox-modulated pathways in inflammatory skin diseases. Free Radical Biology and Medicine. 30: 337-353.
Griffin C.E. & DeBoer D.J. 2001. The ACVD task force on canine atopic dermatitis (XIV): clinical manifestations of canine atopic dermatitis. Veterinary Immunology and Immunopathology. 81: 255-269.
Grotto D., Santa Maria L., Valentini J., Paniz C., Schmitt G., Garcia S.C., Pomblum V.J., Rocha J.B.T. & Farina M. 2009. Importance of the lipid peroxidation biomarkers and methodological aspects for malondialdehyde quantification. Química Nova. 32: 169-174.
Ji H. & Li X.K. 2016. Oxidative Stress in Atopic Dermatitis. Oxidative Medicine and Cellular Longevity : 1-8.
Jiang Y. & Wencong Ma. 2017. Assessment of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Atopic Dermatitis Patients. Medical Science Monitor. 23: 1340-1346.
Kann R.K.C., Seddon J.M., Henning J. & Meers J. 2012. Acute phase proteins in healthy and sick cats. Research in Veterinary Science. 93: 649-654.
Kapun A.P., Salobir J., Levart A., Kotnik T. & Svete A.K. 2012. Oxidative Stress Markers in canine atopic dermatitis. Research Veterinary Science. 92: 469-470.
Kinoshita H., Watanabe K., Azma T., Feng G.G., Akahori T., Hayashi H., Sato M., Fujiwara Y. & Wakatsuki A. 2017. Human serum albumin and oxidative stress in preeclamptic women and the mechanism of albumin for stress reduction. Heliyon. 3(8): e00369.
Krenn‐Pilko S., Langsenlehner U., Stojakovic T., Pichler M., Gerger A., Kapp K.S. & Langsenlehner T. 2016. The elevated preoperative derived neutrophil‐to‐lymphocyte ratio predicts poor clinical outcome in breast cancer patients. Tumour Biology. 37: 361‐368.
Li W.C., Mo L.J., Shi X., Lin Z.Y., Li Y.Y., Yang Z., Wu C.L., Li X.H., Qin L.Q. & Mo W.N. 2018. Antioxidant status of serum bilirubin, uric acid and albumin in pemphigus vulgaris. Clinical and Experimental Dermatology. 43: 158-163.
Martins G.D.C., de Oliveira Melo Junior O.A., Botoni L.S., Nogueira M.M., Costa-Val A.P., Blanco B.S., Dutra W.O., Giunchetti R.C., Melo M.M. & Lemos D.S. 2018. Clinical-Pathological and immunological biomarkers in dogs with atopic dermatitis. Veterinary Immunology and Immunopathology. 205: 58-64.
Naidoo K., Jagot F., van den Elsen L., Pellefigues C., Jones A., Luo H., Johnston K., Painter G., Roediger B., Lee J., Weninger W., Gros G.L. & Forbes-Blom E. 2018. Eosinophils Determine Dermal Thickening and Water Loss in an MC903 Model of Atopic Dermatitis. Journal of Investigative Dermatology. 138: 2606-2616.
Oh M.S., Hong J.Y., Kim M.N., Kwak, E.J., Kim S.Y., Kim E.G., Lee K.E., Kim Y.S., Jee H.M., Kim S.H., Sol I.S., Park C.O., Kim W.K. & Sohn M.H. 2019. Activated Leukocyte Cell Adhesion Molecule Modulates Th2 Immune Response in Atopic Dermatitis. Allergy Asthma and Immunology Research. 11: 677-690.
Olivry T., Saridomichelakis M., Nuttall T., Bensignor M., Griffin C.E. & Hill P.B. 2014. Validation of the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-4, a simplified severity scale for assessing skin lesions of atopic dermatitis in dogs. Veterinary Dermatology. 25: 77-e25.
Pierezan F., Olivry T., Paps J.S., Lawhon S.D., Wu J., Steiner J.M., Suchodolski J.S. & Rodrigues-Hoffmann A. 2016. The skin microbiome in allergen-induced canine atopic dermatitis. Veterinary Dermatology. 27(5): 332-e82.
Pierini A., Gori E., Lippi I., Ceccherini G., Lubas G. & Marchetti V. 2019. Neutrophil-to-lymphocyte ratio, nucleated red blood cells and erythrocyte abnormalities in canine systemic inflammatory response syndrome. Research in Veterinary Science. 126: 150-154.
Rodrigues-Hoffmann A., Patterson A.P., Diesel A., Lawhon S.D., Ly, H.J., Stephenson C.E., Mansell J., Steiner J.M., Dowd S.E., Olivry T. & Suchodolski J.S. 2014. The Skin Microbiome in Healthy and Allergic Dogs. Plos One. 9: e83197.
Sadik C.D., Kim N.D. & Luster A.D. 2011. Neutrophils cascading their way to inflammation. Trends in Immunology. 32: 452-460.
Santoro D., Marsella R., Pucheu-Haston C.M., Eisenschenk M.N., Nutall T. & Bizikova P. 2015. Review: pathogenesis of canine atopic dermatitis: skin barrier and host-micro-organism interaction. Veterinary Dermatology. 26: 84-e25.
Sastre B., Rodrigo-Muñoz J.M., Garcia-Sanchez D.A., Cañas J.A. & Del Pozo V. 2018. Eosinophils: old players in a new game. Journal of Investigational Allergology and Clinical Immunology. 28: 289-304.
Shi G., Zhao J. & Ming L. 2017. Clinical significance of peripheral blood neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients with asthma. Journal of Southern Medical University. 37(1): 84-88.
Shibama S., Ugajin T., Yamaguchi T. & Yokozeki H. 2019. Bilirubin oxidation derived from oxidative stress is associated with disease severity of atopic dermatitis in adults. Clinical and Experimental Dermatology. 44(2): 153-160.
Thijs J.L., Strickland I., Bruijnzeel-Koomen C.A.F.M., Nierkens S., Giovannone B., Knol E.F., Csomor E., Sellman B.R., Mustelin T., Sleeman M.A., Bruin-Weller M.S., Herath A., Drylewicz J., May R.D. & Hijnen D. 2018. Serum biomarker profiles suggests that atopic dermatitis is a systemic disease. Journal of Allergy and Clinical Immunology. 141(4): 1523-1526.
Weidinger S., Beck L.A., Bieber T., Kabashima K. & Irvine A.D. 2018. Atopic Dermatitis. Nature Reviews Disease Primers. 4: 1-20.
Wilson S.R., The L., Batia L.M., Beattie K., Katibah G.E., McClain S.P., Pellegrino M., Estadian D.M. & Bautista D.M. 2013. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 155: 285-295.
Wong C.K., Hu S., Cheung P.F.Y. & Lam C.W.K. 2010. Thymic Stromal Lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. American Journal of Respiratory Cell and Molecular Biology. 43: 305-315.
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